Nucleic Acid Backbone Structure Variations: Peptide Nucleic Acids

Abstract

Synthetic analogues and mimics of the natural genetic material deoxyribonucleic acid (DNA) are potential gene therapeutic
(antisense or antigene) drugs. One of these mimics, peptide nucleic acids (PNAs), are chemically closer to peptides and proteins
than to DNA, but nonetheless have retained many of the structural properties of DNA. These molecules have found applications
as probes in genetic diagnostics and are also being developed into antisense (ribonucleic acid (RNA) interference) gene therapeutic
drugs, targeting selected genes through sequence‐specific recognition of (messenger or micro)RNA, and in the future also antigene
applications targeting the double‐stranded DNA of the genes themselves leading to gene silencing or guiding specific gene
repair. Finally, the special chemical and structural properties of PNA suggest that these or similar molecules might have
played a role in the prebiotic origin of life (on Earth) and also could be interesting components of possible artificial life.

Key Concepts:

Peptide nucleic acid (PNA) is a DNA mimic in which the backbone consists of a charge neutral pseudo peptide.

Peptide nucleic acids can be designed to bind sequence selectively to duplex DNA and thus may function as ‘antigene’ drugs.

A range of chemical structures can mimic various functions of our genetic material, the DNA.

Chemical modifications and structural mimics of DNA are useful as genetic diagnostic probes and are being developed into gene
therapeutic drugs.

Chemical structures of peptide nucleic acid (PNA) in comparison with DNA and a natural peptide. The resemblance of PNA to both peptides and DNA is apparent. However, chemically, PNA is synthesised and ‘behaves’ like a peptide. ‘B’ signifies a nucleobase: adenine (A), cytosine (C), guanine (G) or thymine
(T), and ‘R’ is an amino acid side‐chain.

Binding modes of peptide nucleic acid (PNA) when targeting double‐stranded DNA. At present, most studies have been concerned with the extremely stable triplex invasion
complexes. The ladder represents a schematic DNA double helix and PNA oligomers are shown in bold. The triplex (a) and triplex invasion complexes (b) require a homopurine target and thus a homopyrimidine
PNA. Because the double duplex complex (d) requires two sequence‐complementary PNAs that would normally bind to each other, these
PNAs have to be constructed with ‘pseudo‐complementary’ bases (Lohse et al., ). The duplex invasion complex (c) can, in principle, form with any sequence PNA. However, for unmodified PNA the formed PNA–DNA complexes are not very stable, but the complex can be significantly stabilized using gamma‐PNAs, having a substituent
(e.g. R=–CH3 or –CH2(CH2CH2O)2CH3) in the γ‐position in the backbone (see Figure , ‘R’ in PNA) (e) the nucleobases in PNA–DNA–PNA triple helices are arranged in base triplets via (A‐T and G‐C) Watson‐Crick and (A‐T and GC+ (protonated C)) Hoogsteen base
pairing. PNA is shown in red, DNA in black. Pseodoiso C is a cytosine analogue that does not require protonation) (Sahu et al., ).

Figure 4.

Schematic drawing of the principle of antisense inhibition of translation. Following the ‘central dogma’, the DNA of a gene
is transcribed into a mRNA copy, which is subsequently translated into the functional gene product, a protein. The antisense
reagent interferes with this process by binding to a short region (15–20 nucleotides) of the target mRNA, thereby causing
degradation of the RNA (e.g. via ribonuclease H), or by physically blocking the ribosomal translation process, and thereby
inducing nonsense‐mediated mRNA decay.

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